The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link through Mitochondrial Reactive Oxygen Species

作者：Hung‐Yu Lin, Shao‐Wen Weng, Yen‐Hsiang Chang, Yu‐Jih Su, Chih‐Min Chang, Chia-Jen Tsai, Feng‐Chih Shen, Jiin‐Haur Chuang, Tsu‐Kung Lin, Chia‐Wei Liou, Ching‐Yi Lin, Pei‐Wen Wang · 发表于：Oxidative Medicine and Cellular Longevity · 年份：2018 · DOI：10.1155/2018/7514383 · 被引用次数：85 · 研究领域：Mitochondrial Function and Pathology、Adipose Tissue and Metabolism、Advanced Glycation End Products research

BACKGROUND: Mitochondrial dynamics (mtDYN) has been proposed as a bridge between mitochondrial dysfunction and insulin resistance (IR), which is involved in the pathogenesis of type 2 diabetes (T2D). Our previous study has identified that mitochondrial DNA (mtDNA) haplogroup B4 is a T2D-susceptible genotype. Using transmitochondrial cybrid model, we have confirmed that haplogroup B4 contributes to cellular IR as well as a profission mtDYN, which can be reversed by antioxidant treatment. However, the causal relationship between mtDYN and cellular IR pertaining to T2D-susceptible haplogroup B4 remains unanswered. METHODS: To dissect the mechanisms between mtDYN and IR, knockdown or overexpression of MFN1, MFN2, DRP1, and FIS1 was performed using cybrid B4. We then examined the mitochondrial network and mitochondrial oxidative stress (mtROS) as well as insulin signaling IRS-AKT pathway and glucose transporters (GLUT) translocation to plasma membrane stimulated by insulin. We employed Drp1 inhibitor, mdivi-1, to interfere with endogenous expression of fission to validate the pharmacological effects on IR. RESULTS: Overexpression of MFN1 or MFN2 increased mitochondrial network and reduced mtROS, while knockdown had an opposing effect. In contrast, overexpression of DRP1 or FIS1 decreased mitochondrial network and increased mtROS, while knockdown had an opposing effect. Concomitant with the enhanced mitochondrial network, activation of the IRS1-AKT pathway and GLUT translocation st...